Ketamine Rapidly Reduces Suicidal Ideation

Megan Brooks

December 13, 2017

A subanesthetic intravenous infusion of ketamine can rapidly reduce suicidal ideation in patients with major depression, and the clinical improvement is maintained 6 weeks later, results of a randomized controlled study suggest.

This study is "the most definitive demonstration so far of a clinically meaningful reduction in suicidal ideation within 24 hours after ketamine treatment," first author Michael Grunebaum, MD, from New York State Psychiatric Institute, Columbia University Medical Center, New York City, told Medscape Medical News.

The study was published online December 5 in the American Journal of Psychiatry.

Largest Study to Date

The study included 80 patients who were admitted voluntarily to an inpatient research unit at New York State Psychiatric Institute with major depressive disorder and clinically significant suicidal ideation (Scale for Suicidal Ideation [SSI] score ≥4).

Forty patients were randomly allocated to receive intravenous racemic ketamine hydrochloride 0.5 mg/kg, and 40 patients were allocated to receive midazolam 0.02 mg/kg in 100-mL normal saline infused over 40 minutes. Midazolam was chosen as the comparator because it is a psychoactive anesthetic with a similar half-life to ketamine and has no established antidepressant or antisuicidal effects.

Baseline characteristics were similar in the two groups, including the SSI score. The mean SSI score was 14.3 in the ketamine group and 15.7 in the midazolam group.

The average SSI score 24 hours after infusion (primary outcome) was 4.96 points lower in the ketamine group than in the midazolam group (95% confidence interval [CI], 2.33 - 7.59; P < .001). Cohen's d for the difference in mean group change was 0.75, which is a medium effect size.

Treatment response was defined as a reduction of ≥50% in SSI score. The proportion of patients who experienced a treatment response at day 1 was greater in the ketamine arm than in the midazolam arm (55% vs 30%; odds ratio, 2.85; 95% CI, 1.14 - 7.15; P = .024). The number needed to treat was 4.

Notably, the investigators report, the improvement in suicidal ideation largely persisted during the 6-week period of uncontrolled observation. This may be partly explained by the fact that patients continued prior psychotropic medication, which was optimized after ketamine infusion.

There were greater reductions in overall mood disturbance, depression, and fatigue, as assessed with the Profile of Mood States, on day 1 after ketamine vs midazolam infusion. Results of a mediation model suggest that ketamine's effects on depression and suicidal thoughts are at least partially independent, the researchers note.

Adverse effects (mainly an increase in blood pressure and dissociative symptoms) were similar to those reported in other ketamine studies. The adverse effects were mostly mild to moderate and transient, typically resolving within minutes to hours after infusion, they note.

"This is the largest study to date in suicidal, depressed patients, using a randomized, midazolam-controlled design, and also addressed various prior research limitations, which have included measurement of suicidal ideation with a single questionnaire item and patient samples with low levels of suicidal ideation or mixed diagnoses," Dr Grunebaum told Medscape Medical News.

"We think the most noteworthy results of this study are that it shows, using a rigorous clinical trial design, that ketamine treatment was associated with a clinically meaningful reduction of suicidal thoughts in suicidal, depressed patients within 24 hours and that with optimized, clinical pharmacotherapy in an uncontrolled follow-up observation, this reduction appeared to last for at least 6 weeks," said Dr Grunebaum.

Potential Lifesaver

Reached for comment, Seth A. Mandel, MD, chairman of psychiatry at Northwell Health's Huntington Hospital, New York, said, "There has been a cottage industry of nonpsychiatrists performing ketamine infusions for treatment-refractory depressed patients. My concern in these cases has been, what happens if it fails for someone who has put their last hope in this treatment?

"This study points to a more positive and practical use for ketamine infusions," said Dr Mandel, who was not involved in the study.

"It could be a very useful and even lifesaving temporary maneuver performed in ERs or outpatient ambulatory settings, buying valuable time until treatment can be optimized over the ensuing weeks. It may not only be useful in preventing suicides but also in avoiding costly hospitalizations for acutely suicidal patients," he noted.

Dr Mandel cautioned that it's "unclear from the study what happens with these patients beyond 6 weeks. Does suicidal ideation return, and if so, should the treatments be repeated, and for how long? What are the long-term effects of repeated infusions? Further studies are needed to answer these questions."

The study was supported by the National Institute of Mental Health. Several authors have disclosed financial relationships with various companies, as listed with the original article.

Am J Psychiatry. Published online December 5, 2017. Abstract

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